?NOTE: Updated Abstract March 2016 Defective skeletal patterning is a major contributor of congenital limb malformations, which are among the most frequent birth defects in humans. Loss of epigenetic regulation has been associated with several debilitating human disorders including immune and neurodevelopmental disorders among others. Aberrant DNA modifications either due to mutations in enzymes that catalyze the establishment, maintenance or the readers of these marks are intricately associated with human developmental disorders. Building on Dr. Kota?s previous training and experience in the fields of epigenetic regulation of monoallelic gene expression and stem cell biology, this K01 application will support advanced research training in the interdisciplinary areas of developmental skeletal biology and epigenomics which will enable him to become an independent investigator in the emerging multidisciplinary area of epigenetic regulation of developmental skeletal biology. Specifically, during the K01 award period, Dr. Kota will receive advanced training in 1) theoretical and practical aspects of skeletal development and homeostasis, 2) analysis of mouse models of skeletal disorders and 3) genomic analysis of early limb progenitor cells, from a team of mentors at Harvard University. Training will be completed via formal coursework, hands-on lab training, mentored research and regular attendance at seminars and workshops. Based on the PI's preliminary findings in the mice, the research will focus on elucidating the role of the epigenetic gene regulation during skeletal patterning and aims to evaluate the transcriptome, epigenetic modifications in skeletal progenitors. In summary, the overall goal of the proposal is to understand the epigenetic regulation and its key targets during embryonic skeletal development to get better insights into human congenital limb abnormalities that eventually will lead to better therapeutic avenues.